Urs-12-en-3β-ol, acetate/Urs-12-en-3-ol, acetate, (3β)-/Acetic acid,4,4,6a,6b,8a,11,12,14b-octamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydro-picen-3-yl ester/Urs-12-en-3β-ol, acetate (8CI)/(3β)-Urs-12-en-3-yl acetate/4,4,6a,6b,8a,11,12,14b-octamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl acetate/α-Amyrin acetate/Urs-12-en-3-yl acetate
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provides coniferyl ferulate(CAS#:863-76-3) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of coniferyl ferulate are included as well.>> amp version: coniferyl ferulate
ESICM LIVES 2016: part two Milan, Italy. 1-5 October 2016
2016 Sep 29
SRC homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is a cytosolic adaptor protein that plays an important role in the T-cell receptor-mediated T-cell signaling pathway. SLP-76 links proximal receptor stimulation to downstream effectors through interaction with many signaling proteins. Previous studies showed that mutation of three tyrosine residues, Tyr112, Tyr128, and Tyr145, in the N terminus of SLP-76 results in severely impaired phosphorylation and activation of Itk and PLCγ1, which leads to defective calcium mobilization, Erk activation, and NFAT activation. To expand our knowledge of the role of N-terminal phosphorylation of SLP-76 from these three tyrosine sites, we characterized nearly 1000 tyrosine phosphorylation sites via mass spectrometry in SLP-76 reconstituted wild-type cells and SLP-76 mutant cells in which three tyrosine residues were replaced with phenylalanines (Y3F mutant). Mutation of the three N-terminal tyrosine residues of SLP-76 phenocopied SLP-76-deficient cells for the majority of tyrosine phosphorylation sites observed, including feedback on proximal T-cell receptor signaling proteins. Meanwhile, reversed phosphorylation changes were observed on Tyr192 of Lck when we compared mutants to the complete removal of SLP-76. In addition, N-terminal tyrosine sites of SLP-76 also perturbed phosphorylation of Tyr440 of Fyn, Tyr702 of PLCγ1, Tyr204, Tyr397, and Tyr69 of ZAP-70, revealing new modes of regulation on these sites. All these findings confirmed the central role of N-terminal tyrosine sites of SLP-76 in the pathway and also shed light on novel signaling events that are uniquely regulated by SLP-76 N-terminal tyrosine residues.
Signaling events induced by the T-cell receptor (TCR)1 play an essential role in the adaptive immune response, important for T-cell proliferation, differentiation, and cytokine secretion. TCR engagement results in sequential activation of Src kinase Lck and Fyn, which phosphorylates the CD3ζ-chain immunoreceptor tyrosine-based activation motifs (ITAMs) (1). Phosphorylated ITAMs recruit and activate the Syk family protein kinase ZAP-70, which phosphorylates the transmembrane scaffold linker for activation of T cells (2), as well as SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) (3), forming a signalosome complex essential for the assembly of downstream signaling proteins.
SLP-76, as an adaptor protein, lacks intrinsic enzymatic function but serves as an essential protein scaffold, recruiting other proteins for correct localization during T-cell signaling. Studies with SLP-76-deficient mice and SLP-76-deficient T-cell lines revealed a very profound role for SLP-76 in T-cell development and activation (4-7). In SLP-76-deficient Jurkat T cells, defects were observed in phosphorylation and activation of PLCγ1, calcium mobilization, Erk activation, and cytokine gene transcription following TCR ligation (6). SLP-76 consists of three domains: an N-terminal acidic region containing three tyrosine residues, Tyr112, Tyr128, and Tyr145; a central proline-rich region; and a C-terminal SH2 domain (7). Upon TCR activation, SLP-76 is recruited to the linker for activation of T cells signaling complex through binding with GADS (8), nucleating the interaction of signaling proteins, including PLCγ1, Itk, Vav, Nck, and adhesion and degranulation adaptor protein (9). PLCγ1 is recruited to the SLP-76 signaling complex through binding to both LAT and SLP-76. Phosphorylated Tyr145 of SLP-76 is recognized by the SH2 domain of the Tec family kinase Itk, which also binds to the proline-rich domain of SLP-76 (10). This interaction maintains Itk in an active conformation (7). The binding of PLCγ and active Itk to SLP-76 leads to the phosphorylation and activation of PLCγ1 and subsequent generation of the second messengers inositol 1,4,5-trisphosphate and diacylglcycerol (11). SLP-76 also regulates cytoskeletal rearrangement through the assembly of a tri-molecular signaling complex with Vav and Nck (12). In addition, the interaction between the tyrosine-phosphorylated adaptor protein and the SH2 domain of SLP-76 regulates integrin activation (13).
Besides its importance in regulating downstream signaling proteins, we recently revealed that SLP-76 plays an important role in mediating upstream signaling proteins (14). In a phosphoproteomic study examining cells deficient in SLP-76, SLP-76 was required for mediation of the phosphorylation of PAG (14), which transmits negative regulatory signals in complex with Csk (15). In addition, this earlier study revealed that the absence of SLP-76 perturbs the phosphorylation of Lck and, subsequently, a large number of Lck-regulated signaling molecules (i.e. CD3ε, -δ, -γ, and -ζ chains; ZAP-70) (14). These findings led to the hypothesis that SLP-76 mediates both PAG negative feedback and ERK positive feedback of Lck (14).
Phosphorylation of three N-terminal tyrosine residues is essential for the function of SLP-76 (16). Upon phosphorylation by ZAP-70, phosphorylated Tyr112 and Tyr128 bind to SH2 domains of Vav (17-20), Nck (12, 21), and the p85 subunit of phosphatidylinositol 3-kinase (22), whereas phosphorylated Tyr145 is recognized by the SH2 domain of Itk (10). N-terminal tyrosines of SLP-76 are required for the TCR-induced phosphorylation and activation of Itk and PLCγ1 (7).
However, the current understanding of N-terminal tyrosines of SLP-76 is incomplete, especially regarding their role in the newly discovered feedback regulation of the phosphorylation of upstream signaling proteins. For further elucidation of the function of SLP-76 N-terminal tyrosines in the regulation of the TCR signaling pathway, a wide-scale view of temporal changes in TCR signaling components is required. Quantitative mass-spectrometry-based phosphoproteomics is a powerful way to achieve this goal by enabling the system-wide identification of sites on proteins phosphorylated in the T cell, as well as the quantification of protein phosphorylation (14, 23-28). In this study, a wide-scale quantitative phosphoproteomic method was used to identify TCR-responsive tyrosine phosphorylation sites and to gain system-wide insight into the role of N-terminal tyrosine residues of SLP-76 in the TCR signaling pathway.
SRC Homology 2 Domain-containing Leukocyte Phosphoprotein of 76 kDa (SLP-76) N-terminal Tyrosine Residues Regulate a Dynamic Signaling Equilibrium Involving Feedback of Proximal T-cell Receptor (TCR) Signaling*
Qinqin Ji,‡ Yiyuan Ding,‡ and Arthur R. Salomon‡§¶
Quorum sensing (QS) is a cell-to-cell communication system that uses autoinducers as signaling molecules to enable inter-species and intra-species interactions in response to external stimuli according to the population density. QS allows bacteria such as Acinetobacter baumannii to react rapidly in response to environmental changes and hence, increase the chances of survival. A. baumannii is one of the causative agents in hospital-acquired infections and the number of cases has increased remarkably in the past decade. In this study, A. baumannii strain 863, a multidrug-resistant pathogen, was found to exhibit QS activity by producing N-acyl homoserine lactone. We identified the autoinducer synthase gene, which we named abaI, by performing whole genome sequencing analysis of A. baumannii strain 863. Using high resolution tandem triple quadrupole mass spectrometry, we reported that abaI of A. baumannii strain 863 produced 3-hydroxy-dodecanoyl-homoserine lactone. A gene deletion mutant was constructed, which confirmed the functionality of abaI. A growth defect was observed in the QS-deficient mutant strain. Transcriptome profiling was performed to determine the possible genes regulated by QS. Four groups of genes that showed differential expression were discovered, namely those involved in carbon source metabolism, energy production, stress response and the translation process.
Acinetobacter baumannii, quorum sensing, transcriptomic, RNA-Seq, recombineering, mutagenesis
Characterization and Transcriptome Studies of Autoinducer Synthase Gene from Multidrug Resistant Acinetobacter baumannii Strain 863
Chung-Kiat Ng,1 Kah-Yan How,2 Kok-Keng Tee,1 and Kok-Gan Chan2,3,*